Method for treating asthma using optically pure R(-) albuterol

ABSTRACT

The optically pure R(-) isomer of albuterol, which is substantially free of the S(+) isomer, is a potent bronchodilator for relieving the symptoms associated with asthma in individuals. A method is disclosed utilizing the optically pure R(-) isomer of albuterol for treating asthma while minimizing the side effects associated with albuterol.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 08/163,581,filed Dec. 7, 1993 and now U.S. Pat. No. 5,362,755, which was acontinuation of application Ser. No. 07/896,725, filed Jun. 9, 1992, nowabandoned, which was a continuation of application Ser. No. 07/461,262filed Jan. 5, 1990, now abandoned.

BACKGROUND

Albuterol is a drug belonging to the general class of beta-adrenergiccompounds. The prime action of beta-adrenergic drugs is to stimulateadenyl cyclase, the enzyme which catalyzes the formation ofcyclic-3',5'-adenosine monophosphate (AMP) from adenosine triphosphate(ATP). The cyclic AMP formed mediates the cellular responses. Albuterolacts selectively on beta₂ -adrenergic receptors to relax smooth muscletissue, for example, in the bronchial system. Albuterol is most commonlyused to treat bronchial spasms associated with asthma and is the activecomponent in well-known commercial bronchodilators such as Proventil andVentolin.

The form in which albuterol is presently used is a racemic mixture. Thatis, it is a mixture of optical isomers, called enantiomers. Enantiomersare structurally identical compounds which differ only in that oneisomer is a mirror image of the other and the mirror images cannot besuperimposed. This phenomenon is known as chirality. Most biologicalmolecules exist as enantiomers and exhibit chirality. Althoughstructurally identical, enantiomers can have profoundly differenteffects in biological systems: one enantiomer may have a specificbiological activity while the other enantiomer has no biologicalactivity at all, or may have an entirely different form of biologicalactivity.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating bronchialdisorders, such as asthma, in an individual, by administering to theindividual an amount of optically pure R(-) albuterol which is active inbronchial tissue sufficient to reduce bronchial spasms associated withasthma while minimizing side effects associated with albuterol. Themethod is particularly useful in treating asthma while reducing sideeffects, such as central nervous system stimulatory effects and cardiacarrythmia. In these applications, it is important to have a compositionwhich is a potent broncho-dilator and which does not exhibit the adverseside effects of many beta-adrenergic drugs. A composition containing thepure R(-) isomer of albuterol is particularly useful for thisapplication because this isomer exhibits these desired characteristics.The present method provides a safe, effective method for treating asthmawhile reducing undesirable side effects, for example, tremor,nervousness, shakiness, dizziness and increased appetite, andparticularly, cardiac arrythmia, typically associated withbeta-adrenergic drugs. In children, side effects such as excitement,nervousness and hyperkinesia are reduced when the pure isomer isadministered. In addition to the above, at certain levels racemicalbuterol can cause teratogenic effects, which are believed to beassociated with the S(+) isomer. Administering the pure isomer reducesthe teratogenic potential which is associated with the S(+) isomer ofalbuterol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relies on the bronchodilation activity of the R(-)enantiomer of albuterol to provide relief from bronchial disorders,while simultaneously reducing undesirable side effects, for example,central nervous system stimulatory effects and cardiac disorders,commonly experienced by albuterol users. In the present method, theoptically pure R(-) isomer of albuterol, which is substantially free ofthe S(+) enantiomer, is administered alone, or in combination with oneor more other drug(s) in adjunctive treatment, to an individual in whomasthma relief (e.g., relief from bronchial spasms, shortness of breath)is desired. The optically pure R(-) isomer of albuterol as used hereinrefers to the levorotatory optically pure isomer of α¹[(tert-butylamino) methyl]-4-hydroxy-m-xylene-α, α'-diol, and to anybiologically acceptable salt or ester thereof. The terms "opticallypure" or "substantially free of the S(+) enantiomer" as used hereinmeans that the composition contains at least 90% by weight of the R(-)isomer of albuterol and 10% by weight or less of the S(+) isomer.Optically pure albuterol is readily obtainable by methods known to thoseof skill in the art, for example, by synthesis from an optically pureintermediate.

In the present method, the R(-) isomer of albuterol is administered toan individual who has asthma. For example, R(-) albuterol isadministered to an individual after onset of asthma to reduce breathingdifficulty resulting from asthma. In another embodiment, optically pureR(-) albuterol is administered prophylactically, that is, before thebronchiospasm begins in an asthma attack, to prevent its occurrence orto reduce the extent to which it occurs.

In the present method, R(-) albuterol can be administered by inhalation,by subcutaneous or other injection, orally, intravenously, topically,parenterally, transdermally, rectally or via an implanted reservoircontaining the drug. The form in which the drug will be administered(e.g., inhalant, powder, tablet, capsule, solution, emulsion) willdepend on the route by which it is administered. The quantity of thedrug to be administered will be determined on an individual basis, andwill be based at least in part on consideration of the individual'ssize, the severity of the symptoms to be treated and the result sought.In general, quantities of optically pure R(-) albuterol sufficient toreduce the symptoms of asthma will be administered. The actual dosage(quantity administered at a time) and the number of administrations perday will depend on the mode of administration, for example, by inhaler,nebulizer or oral administration. About 30 mcg to about 90 mcg of theoptically pure R(-) isomer of albuterol given by inhalation one or moretimes per day will be adequate in most individuals to produce thedesired bronchodilation effect. For oral administration, e.g., tablet orsyrup, a dose of about 1 mg to about 8 mg two to four times daily isadministered to produce the desired effect.

In the method of the present invention, the optically pure R(-) isomerof albuterol can be administered together with one or more otherdrug(s). For example, an antiasthmatic drug such as theophylline orterbutaline, or an antihistamine or analgesic such as aspirin,acetaminophen or ibuprofen, can be given with or in close temporalproximity to administration of optically pure, R(-) albuterol. The two(or more) drugs (the optically pure active isomer of albuterol andanother drug) can be administered in one composition or as two separateentities. For example, they can be administered in a single capsule,tablet, powder, or liquid, etc. or as individual compounds. Thecomponents included in a particular composition, in addition tooptically pure albuterol and another drug or drugs, are determinedprimarily by the manner in which the composition is to be administered.For example, a composition to be administered in inhalent form caninclude, in addition to the drug(s), a liquid carrier and/or propellent.A composition to be administered in tablet form can include a filler(e.g., lactose), a binder (e.g., carboxymethyl cellulose, gum arabic,gelatin), an adjuvant, a flavoring agent, a coloring agent and a coatingmaterial (e.g., wax or a plasticizer). A composition to be administeredin liquid form can include the combination of drugs and, optionally, anemulsifying agent, a flavoring agent and/or a coloring agent.

In general, according to the method of the present invention, theoptically pure R(-) isomer of albuterol, alone or in combination withanother drug(s), is administered to an individual periodically asnecessary to reduce symptoms of asthma.

The present composition and method provide an effective treatment forasthma while minimizing the undesirable side effects associated withalbuterol use. These side effects include central nervous systemeffects, such as tremor, nervousness, shakiness, dizziness and increasedappetite, and cardiac effects, such as cardiac arrythmia. In children,side effects, such as excitement, nervousness and hyperkinesia, arereduced when the pure isomer is administered. In addition, teratogeniceffects associated with albuterol are believed to reside in the S(+)enantiomer. Thus, administering the pure R(-) isomer may reduce theteratogenic potential associated with albuterol.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed in the scope of the following claims.

We claim:
 1. A method of treating an acute attack of asthma, whilereducing side effects associated with the acute administration ofracemic albuterol, comprising administering to an individual sufferingfrom an acute attack of asthma a quantity of an optically pure R(-)isomer of albuterol sufficient to result in bronchodilation whilesimultaneously reducing undesirable side effects, said R isomer beingsubstantially free of its S(+) isomer.
 2. A method of claim 1 whereinthe amount of the R(-) isomer of albuterol is greater than approximately90% by weight.
 3. A method of claim 2 wherein the amount of the R(-)isomer of albuterol is greater than 99% by weight.
 4. A method of claim1 comprising administering to the individual by inhalation fromapproximately 30 mcg to approximately 90 mcg of the R(-) isomer ofalbuterol per dose.
 5. A method of treating an acute attack of asthma,while reducing side effects associated with the acute administration ofracemic albuterol, comprising administering to an individual sufferingfrom an acute attack of asthma a quantity of an optically pure R(-)isomer of albuterol sufficient to result in bronchodilation whilesimultaneously reducing undesirable side effects, and at least oneadditional drug selected from the group consisting of bronchodilators,antihistamines and analgesics.
 6. A method of claim 5 wherein theanalgesic is selected from the group consisting of: aspirin,acetaminophen and ibuprofen.